Sphingosine-1-phosphate (S1P) is produced by the phosphorylation of sphingosine derived from sphingomyelin, which is a component of cell membranes, by sphingosine kinase. Conventionally, it has been considered that sphingosine-1-phosphate (S1P) is one of the metabolites of sphingolipids. In recent years, it was shown that it plays a role as intercellular messenger through the endothelial differentiation gene (Edg) receptor, which is a G protein-coupled receptor (for example, see Non-patent literature 1).
Edg receptors have been cloned eight subtypes of Edg-1 to 8 to date, and the specificity of S1P ligands differ depending on subtypes. Five subtypes of Edg-1, Edg-3, Edg-5, Edg-6 and Edg-8 are known in an S1P receptor, and also called S1P1, S1P3, S1P2, S1P4 and S1P5, respectively (for example, see Non-patent literature 1).
From various studies on these S1P receptors, it has been reported that S1P receptor modulators exhibiting agonist activity or antagonist activity to these receptors are useful for a wide variety of disease.
Among these S1P receptors, an S1P1 receptor is highly expressed on lymphocytes (T cells and B cells), and it has been considered that the S1P1 receptor play an important role in the process where lymphocytes migrate from the secondary lymph node tissue such as lymph nodes from the research of mouse limitedly defected S1P1 on lymphocytes (for example, see Non-patent literature 2).
It is known that fingolimod (FTY720), which is an agonist of an S1P1 receptor, is converted to an active phosphorylated form (FTY720-P) by sphingosine kinase in vivo, shows a potent agonist action to the S1P1 receptor and induces internalization and degradation of the S1P1 receptor, and act as a functional antagonist. As a result, a migration of lymphocytes from secondary lymph tissues via the S1P1 receptor is inhibited, and the body circulation of lymphocyte is regulated. It is known that fingolimod inhibits a migration from lymph nodes based on the same mechanism with respect to antigen-specific T cells including autoreactive T cells (for example, see Non-patent literature 3). Therefore, S1P1 receptor agonists are considered to be useful as an agent for the treatment of autoimmune diseases, inflammatory bowel disease, acute or chronic rejection on allo- or xenogeneic tissue or organ transplantation, graft-versus-host disease and the like (for example, see Non-patent literature 4).
However, bradycardia, which is considered to be specific side effects associated with S1P1 receptor agonists, is recognized in fingolimod and become problems (for example, see Non-patent literature 5).
It has been known that S1P1 receptor antagonists have an inhibitory effect on a migration from the lymph node similar to S1P1 receptor agonists as the result, by antagonizing S1P in vivo in the migration process of lymphocytes from secondary lymph node tissue (for example, see Non-patent literature 6). Therefore, S1P1 receptor antagonists are considered to be useful as an agent for the treatment of autoimmune diseases, inflammatory bowel disease, acute or chronic rejection on allo- or xenogeneic tissue or organ transplantation, graft-versus-host disease and the like.
Also, S1P1 receptor antagonists are considered to be useful as an agent for the treatment of age-related macular degeneration by inhibiting angiogenesis (for example, see Non-patent literature 7).
Also, S1P1 receptor antagonists are considered to be useful as an agent for the treatment of cancer (for example, see Non-patent literature 8).
Therefore, a novel S1P1 receptor antagonist having a potent S1P1 receptor antagonistic activity and improved in bradycardia has been desired.
Patent literature 1 discloses a compound having an S1P1 receptor antagonisitic activity represented by the general formula (V):
(see patent literature 1). However, a compound of the present invention represented by the general formula (I) is different from the compound represented by the general formula (V) in a chemical structure of the part binding two aromatic rings.